1. Field of the Invention
The present invention relates to novel oxazolidinone derivatives with a difluorophenyl moiety, pharmaceutically acceptable salts thereof, a method for preparing the same, and an antibiotic composition containing the same as an active ingredient.
2. Description of the Related Art
According to statistics in 1992, as many as 68% of methicillin-resistant Staphylococcus aureus (hereinafter referred to as “MRSA”) strains show multidrug-resistance. Vancomycin, the most potent among currently available antibiotics, is the only antibiotic that is inhibitory of multidrug-resistant MRSA. However, a Staphylococcus aureus strain resistant to vancomycin was found in Japan in May, 1997. In fact, much earlier, in the 1980s, the emergence of vancomycin-resistant enterococci (hereinafter referred to as “VRE”) had been reported from hospitals of the U.S.A. and Britain. In the U.S.A., VRE has increased to 13.6% in 1993 from 0.4% in 1989, and emerged as a hot topic in the medical world. Thus, the effectiveness of the glycopeptide type antibiotic vancomycin, which had been regarded as the last fortress against gram-positive bacteria, was called into doubt.
This great anxiety has disappeared with the emergence of linezolid. Food and Drug Administration (FDA) approval was granted for the antibiotic linezolid (U-100766) in April 2000. It is sold in the U.S. under the trade name Zyvox. Since the quinolone class, 35 years have passed before the development of this novel class antibiotic.
To date, a wide spectrum of various classes of antibiotics is available and various strains are also observed to have resistance thereto. With the expansion of the use of antibiotics, bacteria themselves undergo extensive mutations resulting in an explosive increase in resistance thereto. Furthermore, more frequent use of various antibiotics leads to a higher complexity of antibiotic resistance than in the past.
The antibiotic activity of the oxazolidinone class compounds was first discovered by researchers at E.I. DuPont. This company synthesized the oxazolidionone compounds in 1987 and reported that Dup-721 showed inhibitory activity against Gram-negative anaerobes and Mycobacterium tuberculosis as well as gram-positive strains including MRSA and MRSE.

However, studies on Dup-105 and Dup-721 were not further undertaken because fatal toxicity was observed in conjunction therewith in Stage 1 of clinical testing conducted by Upjohn. Based on the finding that oxazolidinone compounds have antibacterial activity, Upjohn succeeded in developing antibiotic compounds U-100766 (Linezolid) and U-100562 (Eperezolid) in 1996. These compounds are similar to vancomycin in antibacterial activity against Gram-positive strains, but show very poor inhibitory activity against Gram-negative strains.
At this time, it is necessary to develop novel antibiotics as various bacterial strains are resistant to most antibiotics currently being used clinically. Particularly, novel oxazolidinone antibiotics are imperatively needed to circumvent the problem of resistant strains.
Culminating in the present invention, with the goal of overcoming the problems encountered in the prior art, intensive and thorough research was conducted by the present inventors into novel oxazolidinone class antibiotics with more potent anti-bacterial activity, which resulted in the finding that oxazolidinone derivatives with difluorophenyl moieties are highly inhibitory of resistant strains including Gram-positive bacteria and VRE.